Institute of Immunology, Christian-Albrecht-University of Kiel, Arnold-Heller-Str. 3, Kiel, Schleswig-Holstein 24105, Germany.
Institute of Immunology, Christian-Albrecht-University of Kiel, Arnold-Heller-Str. 3, Kiel, Schleswig-Holstein 24105, Germany; Institute of Clinical Molecular Biology, Christian-Albrecht-University of Kiel, Rosalind-Franklin-Str. 12, Kiel, Schleswig-Holstein 24105, Germany.
Immunity. 2022 Oct 11;55(10):1924-1939.e5. doi: 10.1016/j.immuni.2022.08.003. Epub 2022 Aug 12.
SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4 T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4 T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly.
SARS-CoV-2 感染和疫苗接种会产生巨大的宿主反应异质性和免疫反应质量随年龄增长而下降。预先存在的 T 细胞库如何促成这种异质性尚不清楚。我们结合了 SARS-CoV-2 特异性 CD4 T 细胞在接种疫苗前后的分析以及纵向 T 细胞受体追踪。我们发现了强烈的预先存在的 T 细胞变异性，这与随后的免疫反应质量和年龄相关。高质量的反应定义为高亲和力刺突特异性 T 细胞的强烈扩增、高水平的白细胞介素-21 产生和特异性免疫球蛋白 G，取决于完整的幼稚 T 细胞库和排除预先存在的记忆 T 细胞。在老年人中，来自两个隔室的 T 细胞扩增都受到严重损害。我们的研究结果揭示了 CD4 T 细胞库的内在缺陷导致了 SARS-CoV-2 免疫反应质量随年龄增长而下降，并强调了在老年人中需要采用替代策略来诱导针对新出现病原体的高质量 T 细胞反应。
